Bergh 2011 (Continued)
dose the participants were prescribed at inclusion, mean dose at inclusion was 0.92 mg/ d)
Concomitant therapy: all kinds of concomitant therapy were allowed before, during and after the study
Outcomes Primary outcomes: neuropsychiatric symptoms: changes in Neuropsychiatric Inven-
tory-10 (0 weeks, 25 weeks; range 0 to 120), depressive symptoms of a patient with dementia: changes in Cornell’s Depression Scale (0 week, 25 weeks; range 0 to 38), safety analyses: changes on the Unified Parkinson Disease Rating Scale (UPDRS, six- item version) (0 weeks, 25 weeks)
Secondary outcomes: Quality of life - Alzheimer’s disease (QoL-AD), the Severe Im- pairment Battery (SIB), the Lawton & Brody’s Physical Self-Maintenance scale (PSMS) , the Clinical Dementia Rating Scale (CDR)
Notes Sponsor: Innlandet Hospital Trust. There is no conflict of interest of the author reported. It is unclear if the author received grants. Provider of study drugs is not described This was an unpublished study. We requested results by email communication with the author on 8 June 2017 (Van Leeuwen 2017 [pers comm]). We received study results on 10 June 2017. The study arm with antidepressants was published in 2012 as a separate paper. The antipsychotics discontinuation arm was never published as paper. The study results were known in 2011 and reported to the Norwegian Medicines Agency. This study was not included in the 2013 review
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias)
Low risk Comment: participants randomised cen-
trally
Quote: ”...using computer generated ran- domisation (1:1) in block of four...“
Allocation concealment (selection bias) Low risk Comment: pharmacist was responsible for
allocation
Quote: ”... patients were allocated to placebo or active treatment group by cen- tralized allocation in blocks of four (1: 1) by Sykehusapotekene Gjøvik, who also kept the randomisation list, computer de- rived, until the statistical analyses were completed..“
Blinding of participants and personnel (performance bias)
All outcomes
Low risk Comment: study was described as double-
blinded, probably blinding will be success- fully done
Quote: ”Study blinding was maintained as no other involved partner of the study knew the randomisation list than Syke- husapoteket Gjøvik. All statistical analy-
Bergh 2011 (Continued)
ses were performed before the randomisa- tion groups were unblended. The bottles with active medication and placebo were identical labelled...replaced by placebo in a blinded way or replaced by a study drug containing active medication (same kind, same dose) as before...“
Blinding of outcome assessment (detection bias)
All outcomes
Low risk Comment: probably blinding of assess-
ment outcomes was successfully done. The study involved 57 study nurses which could have biased the results
Quote: ”Data collection was done by research nurses. All statistical analyses were performed before the randomisation groups were unblended. A sealed code en- velope was stored in the patient’s medical journal at the nursing homes, and could only be opened in case of medical emergen- cies as a serious adverse event.“
Incomplete outcome data (attrition bias) NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)
High risk Comment: all randomised participants
(19) are described in the flowchart. Very high dropout and withdrawal in the discon- tinuation group (7/9) suggests high risk of bias. Dropouts were more frequent in the ApDG (7/9, 77.8%) than in the ApCG (0/ 10, 0.0%) (P = 0.001). The analysis was based on modified ITT: participants in ef- ficacy analysis: 16, participants included in safety analysis: 18. Unpublished data and high dropouts suggests high risk of attrition bias
Selective reporting (reporting bias) High risk Comment: protocol was registered in Clin-
icalTrials.gov, outcome measurements were not all reported as per protocol paper. Study is unpublished, no peer reviewing to valid results suggests high risk of bias
Quote: ” ... The number of primary end- points were reduced from three to two: Cornell Scale of Depression in Dementia and the Neuropsychiatric Inventory...the changes were made prior to breaking the blind, and have limited implications for study interpretation... no observe case anal- ysis en no interim analyses as planned in the protocol.“
Bergh 2011 (Continued)
Other bias Low risk No other bias
Bridges-Parlet 1997
Methods Design: double-blind, baseline treatment neuroleptic-controlled pilot study
Duration: 4 weeks
Participants Country: USA
Setting: residents of long-term care facilities
Participants: 36 (22 discontinuation, 14 continuation)
Inclusion criteria: participants with diagnosis of possible or probable Alzheimer’s de- mentia (criteria were given), participants receiving a neuroleptic (any traditional neu- roleptic was acceptable) and who had been on a stable dose for 3 months prior to the study, a history of physically aggressive behaviour according to the referring nursing supervisor, participants residing in a nursing home, participants on antidepressants were permitted to participate if medication doses had been stable
Exclusion criteria: participants with primary psychiatric diagnoses, mental retardation and terminal illness or other recent acute, changes in health status (e.g. recent broken hip)
Interventions Intervention 1: withdrawal neuroleptics (discontinuation)
Intervention 2: no withdrawal neuroleptics (continuation)
Abrupt withdrawal or tapering off a neuroleptic when baseline dose exceeded the equiv- alent of 50 mg of chlorpromazine. The tapering was done by dropping the baseline neu- roleptic dose by half during week 1 and then discontinuing the neuroleptic completely at the beginning of week 2
Neuroleptic drugs: haloperidol (21), thioridazine (9), thiothixene (3), trifluoperazine (1) , mesoridazine (1), loxapine (1)
Outcomes Primary outcome: completion of the 4 weeks of study (numbers completing the 4 week
study), behavioural symptoms: change in the amount of observed physically aggressive behaviour (mean, mean difference) (0, 1, 2, 4 weeks)
Secondary outcomes: use of physical restraint, verbally aggressive behaviour, walking, amount of time spent sleeping and sitting, verbal aggressiveness, physically aggressive acts observed by experienced study personnel and by using a portable barcode reader capable of storing several hours of observation (0, 1, 2, 4 weeks)
Notes Research grant from the Alzheimer’s Association.
There may have been selective recruitment limiting the generalisation of the results Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias)
Low risk Comment: randomisation was done by
random number table
Quote: ”Assignment was based on a prede- termined sequence such that three patients
Bridges-Parlet 1997 (Continued)
were assigned to withdrawal for every two not withdrawn. At the end of week 1, sub- jects were randomly assigned to either with- drawal or no withdrawal.“
Allocation concealment (selection bias) Unclear risk Comment: method of allocation conceal-
ment is not described, and may not have been blinded. Participant groups were well matched for age, chlorpromazine-equiva- lent neuroleptic dose and physically aggres- sive behaviour at baseline
Blinding of participants and personnel (performance bias)
All outcomes
Low risk Comment: study is described as double-
blinded, unlikely that blinding could have been broken. Nursing staff was involved in decision to discontinue the programme. They were blinded for the treatment allo- cated, thus outcome assessment may have been adequately blinded
Quote: ”Patients in both groups received identical-appearing capsules prepared at the University of Minnesota Hospital Phar- macy. Patients receiving their medication in crushed form, received in the placebo group tablets of vitamin C instead of cap- sules. The patient receiving intramuscular mesoridazine daily was given intramuscu- lar saline from a nurse not directly involved in the patient’s care“
Blinding of outcome assessment (detection bias)
All outcomes
Low risk Comment: study is described as dou-
ble-blinded, unlikely that blinding could have been broken. Participants were di- rectly observed by study personnel, who were blinded to treatment assignments and recording behaviour was done by using a portable bar-code reader capable of storing several hours of observation
Incomplete outcome data (attrition bias) NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)
Low risk Comment: dropouts were described
Quote: ”Of the 22 patients who were with- drawn, 20 (91%) completed the 4-week double-blinded withdrawal. Two patients were restarted on medication on the rec- ommendation of the nursing staff; only one went back on a neuroleptic. Of the 14 pa- tients not withdrawn, all completed the 4-week trial. Of the 576 observation pe- riods there were seven in which the bar-
Bridges-Parlet 1997 (Continued)
code reader failed. Handwritten back-up notes were used for physically aggressive be- haviour frequency.“
Selective reporting (reporting bias) Low risk Comment: all intended outcomes were re-
ported
Other bias Low risk No other bias
Cohen-Mansfield 1999
Methods Design: double-blind cross-over study
Duration: seven weeks followed by seven weeks cross-over
Participants Country: USA
Setting: residents of one nursing home
Diagnosis: the diagnosis of dementia was not mentioned Number of participants: 58
Inclusion criteria: nursing home residents; aged over 70 years; had received at least four weeks haloperidol, thioridazine or lorazepam for agitation
Exclusion criteria: concomitant administration of other antipsychotic or anti-anxiety drugs other than low-dose trazodone hydrochloride for sleep, life expectancy less than three months due to obvious causes as judged by the nursing home staff member respon- sible for direct care psychiatric diagnosis of a major affective disorder of schizophrenia according toDSM-III, acute infection within 10 days before entry, expectancy of leaving the nursing home within three months, uncontrolled hyperglycaemia or hypoglycaemia Interventions Tapering period: withdrawal of antipsychotic and lorazepam use by tapering to placebo
during a three-week period
Intervention 1: seven weeks of taking placebo followed by seven weeks of taking an- tipsychotic medication
Intervention 2: seven weeks of taking medication followed by seven weeks of placebo Antipsychotics: haloperidol, thioridazine
Outcomes Time of measurements: one week after start of dosage tapering (week 1), phase one
tapering (week 3), phase one end point (week 10), phase two tapering (week 13), phase two end point (week 20)
Primary outcomes: behavioural symptoms (BPRS) (mean), agitation (CMAI) (mean) Secondary outcomes (mean): adverse effects (AIMS), cognitive function (MMSE), global impression scale (GCI-S), sleep and activity level ratings
Time of assessment: one week after start of dosage tapering (week 1), phase one tapering (week 3), phase one end point (week 10), phase two tapering (week 13), phase two end point (week 20)
Notes Several different analyses were used to assess the robustness of the result. However, it was not clear if an intention-to-treat analysis was used. We were unable to use any data from this study.Cohen-Mansfield 1999did not report outcome data separately for the different medications discontinued in the trial (which included the benzodiazepine
Cohen-Mansfield 1999 (Continued)
lorazepam as well as the antipsychotics haloperidol and thioridazine)
This study was supported by grants AG00547 and AG10172 from the National Institute on Aging, Bethesda, MD, USA
No conflicts of interest reported.
Because diagnosis of dementia was not mentioned in the paper, we emailed the first author (Declerck 2009a [pers comm]on 21 april 2009 to ask her whether the participants included had dementia and her answer was positive (referring to the MMSE scores) We have asked the author by email for more results (SDs of the means…) on 1 July 2009, but we have not received any response on our last e-mail (Declerck 2009b [pers comm]).
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias)
Unclear risk Comment: method of sequence generation
is not described
Quote ”...half the residents were randomly assigned to have their medication dose ta- pered during a 3-week period, followed by receipt of a placebo (the other half continued their usual medication dosage) . Residents were randomly assigned to the placebo versus medication group and strat- ified both by level of cognitive function and by psychotropic medication.“
Allocation concealment (selection bias) Unclear risk Comment: allocation is not described
Blinding of participants and personnel (performance bias)
All outcomes
Low risk Comment: study is described as blinded,
unlikely that blinding was broken Quote: ”Study medications (usual medi- cation and placebo) were administered as identical liquids to ensure blindness by the care team. Only the dispensing pharma- cist, who was not an employee of the nurs- ing home, knew which medication was ad- ministered. The care team, residents, family caregivers, and research team were blinded to which group a participant was assigned. “
Blinding of outcome assessment (detection bias)
All outcomes
Low risk Comment: study is described as blinded,
unlikely that blinding was broken Quote: ”The care team, ... and research team were blinded to which group a partic- ipant was assigned. Primary outcome data BPRS was assessed by daytime and evening nursing staff. “
Cohen-Mansfield 1999 (Continued)
Incomplete outcome data (attrition bias) NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)
Unclear risk Comment: rates and reason for dropout
were described. However we were uncertain how many participants discontinued in the discontinuation or continuation group in the first part of the study
Quote: ”Twenty-three participants discon- tinued participation in the study before completion for the following reasons: death or dying (3), hospitalisation (1), not eating or weight loss (3), increased agitation (9) , lethargy (2), withdrawal of consent (4), facial asymmetry (1) and fall (3); some had multiple reasons. For 12 participants, dis- continuation occurred during the original drug dosage, for 9 while taking placebo, and for 2 during titration from drug to placebo. Most discontinuations (20 of 23) occurred in the first part of the study, be- fore the cross-over.“
Selective reporting (reporting bias) High risk Comment: no distinction is made for num-
ber of withdrawals in each group during the first part of the trial. it is not clear how they analyse these outcome. By not making difference in outcome reporting between discontinuation of antipsychotics, namely haloperidol and thioridazine, ver- sus discontinuation of lorazepam, a benzo- diazepine, it is impossible to retain robust conclusions from this withdrawal study Quote: ”Participants who discontinued the study were similar in demographic char- acteristics to those who stayed. Although their levels of agitation at baseline were higher than those who stayed in the study, these differences did not reach statistical significance. Most withdrawals from the study occurred in the first part of the study (no numbers given).“
Devanand 2011
Methods Design: a six-month, randomised, double-blind, placebo-controlled discontinuation trial (phase B) following response to haloperidol open treatment during 20 weeks (phase A)
Participants Country: USA
Setting: participants living in the community who presented to a memory disorders clinic or an affiliated behavioural neurology practice group
Total number of participants: 44 participants included in phase A, 22 responders of phase A were eligible for randomisation in phase B (discontinuation trial), 20 in phase B (10 discontinuation, 10 continuation)
Gender distribution (female): 77% Mean (years): 75 (SD 8.0)
Inclusion criteria: aged 50 to 95 years, clinical diagnosis of dementia byDSM-IVcriteria and probable Alzheimer’s disease by NNCDS-ADRA criteria, MMSE range between 5 and 26, current symptoms of psychosis, agitation or aggression
Exclusion criteria: acute unstable medical condition, delirium, alcohol or substance abuse or dependence during the prior year, clinical evidence of stroke, other dementias including vascular or Lewy body or frontotemporal dementia, multiple sclerosis, Parkin- son’s disease, Huntington’s disease, tardive dyskinesia, diagnosis of a psychotic disorder predating the onset of dementia, antipsychotic medication usage during the 4 weeks before study entry, and contra-indication to the use of haloperidol
Interventions Phase A: open treatment (20 weeks): 44 participants living in the community with Alzheimer’s disease and psychosis, agitation or aggression receiving psychotropic medi- cation had a 1-week washout before entering phase A. During phase A flexible doses of haloperidol 0.5 to 5 mg daily were individually titrated to maximise therapeutic response and minimise side effects, especially extrapyramidal side effects. Visits occurred at 0, 2, 4, 8, 12, 16 and 20 weeks
Phase B: discontinuation trial (24 weeks): 20 phase A responders were double-blind ran- domised to a continuation versus placebo (i.e. discontinuation) group. For participants randomised to placebo, there was a 2-week double-blind sequential placebo substitution tapering period to placebo
Outcomes Phase A: the 3 most prominent targets of psychosis, agitation or aggression, scored on a 7-point scale (0 = absent to 6 = extreme) and tracked during the study. Criteria for response (primary outcome) were minimum 50% reduction from baseline in the sum score of these 3 target symptoms, a sum score ≤ 6 on these 3 items (range 0 to 18), and minimal or greater improvement on the CGI-C score (rated only for symptoms of psychosis, agitation or aggression)
Phase B
Primary outcome: relapse, assessed at any single time point during phase B. Criteria for relapse were minimum 50% worsening from the sum score of the 3 target symptoms at the end of phase A, a sum score ≥ 6 on these 3 items (range 0 to 18), and minimal or greater worsening on the CGI-C score (rated for psychosis and agitation/aggression) Secondary outcomes: somatic side effects assessed by the TESS, extrapyramidal signs assessed by the UPDRS and tardive dyskinesia assessed by the Rockland TD scale. Cognition was assessed by change in MMSE and impairment in ADL was assessed by the modified BFAS
Time points of assessment during phase B: 0 (same as end of phase A), 2, 4, 8, 12, 16, 20 and 24 weeks (i.e. 6 months)
Devanand 2011 (Continued)
Pretrial: a 1-week washout prior to entering phase A.
Notes Disclosures: authors had financial links with several pharmaceutical companies. Study
supported by NIH grant
The discontinuation trial included only participants who responded to haloperidol. Non- responders after the first 20 weeks (phase A) were excluded from the discontinuation phase (B). This limits the generalisability of the results
Risk of bias
Bias Authors’ judgement Support for judgement
Random sequence generation (selection bias)
Unclear risk Comment: not described in the study
Allocation concealment (selection bias) Unclear risk Comment: no description of the blinding
of random allocation
Quote: ”Responders by end-Phase A were eligible for Phase B, a 24-week, random assignment (1:1 assignment of haloperidol and placebo), double-blind, trial of contin- uation haloperidol (same dose as end-Phase A) versus switch to placebo.“
Blinding of participants and personnel (performance bias)
All outcomes
Low risk Comment: study is described as double-
blinded, unlikely blinding could have been broken
Quote: ”Haloperidol and placebo were made up in identical looking opaque white capsules.“
Blinding of outcome assessment (detection bias)
All outcomes
Unclear risk Comment: blinding of outcome raters is
not described. In these trial, they were sev- eral subjective outcomes, so a lack of blind- ing of outcome assessors could had an in- fluence
The protocol (Devanand 2012a) for the subsequent study (Devanand 2012) men- tions: Quote: ”The blind is maintained af- ter study exit to avoid biasing raters. A code-break is authorized only if needed in cases of overdose or medical emergency... raters remained unaware of the group as- signments of all patients during the entire study.“
Incomplete outcome data (attrition bias) NPI (Neuro Psychiatric Inventory) and DCM (Dementia Care Mapping)
Low risk Comment: non-completers data were de-
scribed and balanced between the groups Attrition at end of phase A fully accounted
Devanand 2011 (Continued)
for; quote: ”There were 15 Phase A non- completers (34%), with all early termina- tions attributed either to lack of efficacy (n = 9) or side effects (n = 6).“
Attrition at end of phase B accounted for and ITT included; quote: ”Twenty of the 21 patients randomised in Phase B to con- tinuation haloperidol or placebo had at least one follow-up visit after randomisa- tion and were included in the Phase B anal- ysis. Among patients who did not relapse, reasons for early study termination prior to 24 weeks in Phase B were side effects (n = 2), moving out of the area (n = 1), medical illness (n = 1) and noncompliance (n = 1). All data from these patients were included in the intent-to-treat, last observation car- ried forward, analyses. “
Selective reporting (reporting bias) Unclear risk Comment: several outcomes were mea-
sured at baseline of the open haloperidol treatment and at time of the discontinua- tion period, but no results were reported at later times of assessment
Other bias Low risk No other bias
Devanand 2012
Methods Phase A: flexible dose risperidone open treatment for 16 weeks
Phase B: six-month, randomised, double-blind, placebo-controlled discontinuation trial, following response to phase A
Duration: 48 weeks
Participants Country: USA
Setting: outpatients through physician referrals and advertising; and residents of as- sisted-living facilities (memory clinics (including Alzheimer’s research centres), geriatric psychiatry clinics and clinics at Veterans’ Affairs medical centres) or nursing home Total number of participants: 253 participants screened
Phase A: 180 received risperidone, participants who had a response in phase A entered phase B
Phase B: 110 randomised
Group 1: continue risperidone: 32 participants at start, 13 received risperidone at 16